This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Genetic, immunological, and exogenous factors interact to induce pancreatic beta-cells autoimmunity in a small minority of the individuals who have a genetic predisposition to developing insulin-dependent diabetes mellitus (IDDM). Our past studies proved that preclinical IDDM could be identified in children and adults with immune and metabolic markers. They also demonstrated that persistent production of autoantibodies against beta-cell antigens in high-risk individuals almost always commenced prior to the time of study enrollment. We therefore hypothesize that the initiation of the autoimmune cascade and the resultant molecular and cellular changes that culminate in clinical disease, occur in the very early years of life. Because it identifies babies at high risk for Beta-cell autoimmunity prior to their earliest production of autoantibodies, our neonatal genetic screening program provides us with our first chance ever to test the hypothesis in a cohort design.